Substituted isoquinolinones
View Patent ↗Isoquinolinone compounds are provided that are useful for the inhibition of ADP-platelet aggregation, particularly in the treatment of thrombosis and thrombosis related conditions or disorders.
1. A compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein the dotted line represents an optional double bond;
R 1 is a member selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl and benzyl;
R 2 is a member selected from the group consisting of H, C 1-6 alkyl and C 1-6 haloalkyl;
R 3 is a member selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano and —C(O)R 3a , wherein R 3a is a member selected from the group consisting of H, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, C 1-6 alkylamino and di- C 1-6 alkylamino;
R 4 is a member selected from the group consisting of H and C 1-6 alkyl;
R 5 is a member selected from the group consisting of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, cyano and —C(O)R 5a , wherein R 5a is a member selected from the group consisting of C 1-6 alkoxy, amino, C 1-6 alkylamino and di- C 1-6 alkylamino; and
Ar is an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine, each of which is optionally substituted with from 1-2 R 6 substituents,
wherein each R 6 is independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl, C 3-5 cycloalkyl-alkoxy, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, —C(O)R 6a , —O(CH 2 ) m OR 6b , —(CH 2 ) m OR 6b , —O(CH 2 ) m N(R 6b ) 2 and —(CH 2 ) m N(R 6b ) 2 ,
wherein the subscript m is an integer of from 1 to 3, each R 6a is a member independently selected from the group consisting of H, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, C 1-6 alkylamino and di-C 1-6 alkylamino, and each R 6b is a member independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkanoyl, and optionally, two R 6b groups attached to nitrogen are combined with the nitrogen atom to form an azetidine, pyrrolidine or piperidine ring.
2. A compound of claim 1 , having the formula:
wherein the subscript n is an integer of from 0 to 2.
3. A compound of claim 1 , having the formula:
wherein the subscript n is an integer of from 0 to 2.
4. A compound of claim 1 , having the formula:
wherein the subscript n is an integer of from 0 to 2.
5. A compound of claim 2 , wherein n is an integer of from 0 to 2; R 1 is C 1-4 alkyl, C 3-5 cycloalkyl, or C 3-5 cycloalkyl-alkyl; R 2 is H; R 3 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl, C 1-4 haloalkyl, cyano or —C(O)R 3a ; R 4 is H or C 1-4 alkyl; R 5 is halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, —CN, —C≡CH or —CONH 2 ; and R 6 , when present is selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl-alkoxy, —O(CH 2 ) m OR 6b and —O(CH 2 ) m N(R 6b ) 2 wherein the subscript m is 1 or 2 and each R 6b is independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkanoyl.
6. A compound of claim 5 , wherein R 1 is C 1-4 alkyl; R 4 is H or CH 3 ; R 5 is halogen or C 1-4 alkyl; and R 6 when present is selected from C 1-4 alkyl, —O(CH 2 ) m OR 6b and —O(CH 2 ) m N(R 6b ) 2 .
7. A compound of claim 6 , wherein R 1 is methyl; R 5 is chloro, and is attached at the 5-position of the thienyl ring; and R 6 when present is selected from the group consisting of CH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 , —OCH 2 OCH 3 , —OCH 2 CH 2 OC(O)CH 3 and —O(CH 2 ) 2 N(CH 3 ) 2 .
8. A compound of claim 7 , wherein n is 0.
9. A compound of claim 7 , wherein n is 1.
10. A compound of claim 7 , wherein n is 2.
11. A compound of claim 3 , wherein n is 0 or 1; R 1 is C 1-4 alkyl, C 3-5 cycloalkyl, or C 3-5 cycloalkyl-alkyl; R 2 is H; R 3 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl, C 1-4 haloalkyl, cyano or —C(O)R 3a ; R 4 is H or C 1-4 alkyl; R 5 is halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, —CN, —C≡CH or —CONH 2 ; and R 6 , when present is selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl-alkoxy, —O(CH 2 ) m OR 6b and —O(CH 2 ) m N(R 6b ) 2 wherein the subscript m is 1 or 2 and each R 6b is independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkanoyl.
12. A compound of claim 11 , wherein R 1 is C 1-4 alkyl; R 4 is H or CH 3 ; R 5 is halogen or C 1-4 alkyl; and R 6 when present is selected from C 1-4 alkyl, —O(CH 2 ) m OR 6b and —O(CH 2 ) m N(R 6b ) 2 .
13. A compound of claim 12 , wherein R 1 is methyl; R 3 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl or C 3-5 cycloalkyl-alkyl; R 4 is H or CH 3 ; R 5 is chloro and is attached at the 5-position of the thienyl ring; and R 6 , when present is selected from the group consisting of C 1-4 alkyl, —O(CH 2 ) m OR 6b and —O(CH 2 ) m N(R 6b ) 2 wherein the subscript m is 1 or 2 and each R 6b is independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkanoyl.
14. A compound of claim 4 , wherein n is 0 or 1; R 1 is C 1-4 alkyl, C 3-5 cycloalkyl, or C 3-5 cycloalkyl-alkyl; R 2 is H; R 3 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl, C 1-4 haloalkyl, cyano or —C(O)R 3a ; R 4 is H or C 1-4 alkyl; R 5 is halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, —CN, —C≡CH or —CONH 2 ; and R 6 , when present is selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl-alkoxy, —O(CH 2 ) m OR 6b and —O(CH 2 ) m N(R 6b ) 2 wherein the subscript m is 1 or 2 and each R 6b is independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkanoyl.
15. A compound of claim 14 , wherein R 1 is C 1-4 alkyl; R 4 is H or CH 3 ; R 5 is halogen or C 1-4 alkyl; and R 6 when present is selected from C 1-4 alkyl, —O(CH 2 ) m OR 6b and —O(CH 2 ) m N(R 6b ) 2 .
16. A compound of claim 15 , wherein R 1 is methyl; R 3 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl or C 3-5 cycloalkyl-alkyl; R 4 is H or CH 3 ; R 5 is chloro and is attached at the 5-position of the thienyl ring; and R 6 , when present is selected from the group consisting of C 1-4 alkyl, —O(CH 2 ) m OR 6b and —O(CH 2 ) m N(R 6b ) 2 wherein the subscript m is 1 or 2 and each R 6b is independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkanoyl.
17. A compound of claim 1 , selected from the group consisting of:
18. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein the dotted line represents an optional double bond;
R 1 is a member selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl and benzyl;
R 2 is a member selected from the group consisting of H, C 1-6 alkyl and C 1-6 haloalkyl;
R 3 is a member selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano and —C(O)R 3a , wherein R 3a is a member selected from the group consisting of H, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, C 1-6 alkylamino and di-C 1-6 alkylamino;
R 4 is a member selected from the group consisting of H and C 1-6 alkyl;
R 5 is a member selected from the group consisting of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C-6 haloalkyl, C 1-6 alkoxy, cyano and —C(O)R 5a , wherein R 5a is a member selected from the group consisting of C 1-6 alkoxy, amino, C 1-6 alkylamino and di- C-6 alkylamino; and
Ar is an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine, each of which is optionally substituted with from 1-2 R 6 substituents,
wherein each R 6 is independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl, C 3-5 cycloalkyl-alkoxy, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, —C(O)R 6a , —O(CH 2 ) m OR 6b , —(CH 2 ) m OR 6b , —O(CH 2 ) m N(R 6b ) 2 and —(CH 2 ) m N(R 6b ) 2 ,
wherein the subscript m is an integer of from 1 to 3, each R 6a is a member independently selected from the group consisting of H, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, C 1-6 alkylamino and di- C 1-6 alkylamino, and each R 6b is a member independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkanoyl, and optionally, two R 6b groups attached to nitrogen are combined with the nitrogen atom to form an azetidine, pyrrolidine or piperidine ring.
19. A pharmaceutical composition of claim 18 , wherein said compound has the formula:
wherein n is 0 or 1; R 1 is C 1-4 alkyl, C 3-5 cycloalkyl, or C 3-5 cycloalkyl-alkyl; R 2 is H; R 3 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl, C 1-4 haloalkyl, cyano and —C(O)R 3a ; R 4 is H or C 1-4 alkyl; R 5 is halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, —CN, —C≡CH or —CONH 2 ; and R 6 , when present is selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl-alkoxy, —O(CH 2 ) m OR 6b and —O(CH 2 ) m N(R 6b ) 2 wherein the subscript m is 1 or 2 and each R 6b is independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkanoyl.
20. A pharmaceutical composition of claim 19 , wherein R 1 is methyl; R 3 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl or C 3-5 cycloalkyl-alkyl; R 4 is H or CH 3 ; R 5 is chloro and is attached at the 5-position of the thienyl ring; and R 6 , when present is selected from the group consisting of C 1-4 alkyl, —O(CH 2 ) m OR 6b and —O(CH 2 ) m N(R 6b ) 2 wherein the subscript m is 1 or 2 and each R 6b is independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkanoyl.
21. A pharmaceutical composition of claim 18 , wherein said compound is selected from the group consisting of:
22. A method of treating thrombosis in a subject comprising administering to a subject in need thereof, a therapeutically effective amount of a compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein the dotted line indicates an optional double bond;
R 1 is a member selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl and benzyl;
R 2 is a member selected from the group consisting of H, C 1-6 alkyl and C 1-6 haloalkyl;
R 3 is a member selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano and —C(O)R 3a , wherein R 3a is a member selected from the group consisting of H, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, C 1-6 alkylamino and di- C 1-6 alkylamino;
R 4 is a member selected from the group consisting of H and C 1-6 alkyl;
R 5 is a member selected from the group consisting of H, halogen, C 1-6 , alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, cyano and —C(O)R 5a , wherein R 5a is a member selected from the group consisting of C 1-6 alkoxy, amino, C 1-6 alkylamino and di- C 1-6 alkylamino; and
Ar is an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine, each of which is optionally substituted with from 1-2 R 6 substituents,
wherein each R 6 is independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl, C 3-5 cycloalkyl-alkoxy, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, —C(O)R 6a , —O(CH 2 ) m OR 6b , —(CH 2 ) m OR 6b , —O(CH 2 ) m N(R 6b ) 2 and —(CH 2 ) m N(R 6b ) 2 ,
wherein the subscript m is an integer of from 1 to 3, each R 6a is a member independently selected from the group consisting of H, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, C 1-6 alkylamino and di- C 1-6 alkylamino, and each R 6b is a member independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkanoyl, and optionally, two R 6b groups attached to nitrogen are combined with the nitrogen atom to form an azetidine, pyrrolidine or piperidine ring.
23. A method in accordance with claim 22 , wherein said compound is administered in combination with a second therapeutic agent selected from the group consisting of antiplatelet compounds, anticoagulants, fibrinolytics, anti-inflammatory compounds, cholesterol-lowering agents, blood pressure-lowering agents and serotonin blockers.
24. A method in accordance with claim 23 , wherein said second therapeutic agent is an antiplatelet compound selected from the group consisting of GPIIB-IIIa antagonists, aspirin, phosphodiesterase III inhibitors and thromboxane A2 receptor antoagonists.
25. A method in accordance with claim 23 , wherein said second therapeutic agent is an anticoagulant selected from the group consisting of thrombin inhibitors, coumadin, heparin and Lovenox®.
26. A method in accordance with claim 23 , wherein said second therapeutic agent is an anti-inflammatory compound selected from the group consisting of non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors and rheumatoid arthritis agents.
27. A method in accordance with claim 23 , wherein said compound is administered orally.
28. A method in accordance with claim 22 , wherein said compound has the formula:
wherein n is 0 or 1; R 1 is C 1-4 alkyl, C 3-5 cycloalkyl, or C 3-5 cycloalkyl-alkyl; R 2 is H; R 3 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, C 3-5 cycloalkyl-alkyl, C 1-4 haloalkyl, cyano or —C(O)R 3a ; R 4 is H or C 1-4 alkyl; R 5 is halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, —CN, —C≡CH or —CONH 2 ; and R 6 , when present is selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 3-5 cycloalkyl-alkoxy, —O(CH 2 ) m OR 6b and —O(CH 2 ) m N(R 6b ) 2 wherein the subscript m is 1 or 2 and each R 6b is independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkanoyl.
29. A method in accordance with claim 28 , wherein R 1 is methyl; R 3 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl or C 3-5 cycloalkyl-alkyl; R 4 is H or CH 3 ; R 5 is chloro and is attached at the 5-position of the thienyl ring; and R 6 , when present is selected from the group consisting of C 1-4 alkyl, —O(CH 2 ) m OR 6b and —O(CH 2 ) m N(R 6b ) 2 wherein the subscript m is 1 or 2 and each R 6b is independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 alkanoyl.
30. A method in accordance with claim 22 , wherein said compound is selected from the group consisting of: